Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University, China.
Advanced Institute for Medical Sciences, Dalian Medical University, China.
FEBS J. 2020 Feb;287(3):529-545. doi: 10.1111/febs.15042. Epub 2019 Aug 24.
The E3 ubiquitin ligase neural precursor cell-expressed developmentally down-regulated protein 4 (NEDD4) plays a crucial role in governing a number of signaling pathways, including insulin and autophagy signaling. However, the molecular mechanism by which NEDD4 gene is transcriptionally regulated has not been fully elucidated. Here, we reported that NEDD4 mRNA and protein levels were increased by peroxisome proliferator-activated receptor-γ (PPARγ) in HepG2 hepatocytes. PPARγ antagonist GW9662 abolished thiazolidinedione (TZD)-induced NEDD4 expression. ChIP and luciferase reporter assays showed that PPARγ directly bound to the potential PPAR-responsive elements (PPREs) within the promoter region of the human NEDD4 gene. In addition, TZDs increased Akt phosphorylation and glucose uptake, which were abrogated through NEDD4 depletion. Furthermore, we showed that NEDD4-mediated autophagy induction and Akt phosphorylation were suppressed by oleic acid and high glucose treatment, activation of PPARγ successfully prevented this suppression. In conclusion, these results suggest that PPARγ plays a novel role in linking glucose metabolism and protein homeostasis through NEDD4-mediated effects on the autophagy machinery.
E3 泛素连接酶神经前体细胞表达的发育下调蛋白 4（NEDD4）在调节包括胰岛素和自噬信号在内的许多信号通路中发挥着关键作用。然而，NEDD4 基因转录调控的分子机制尚未完全阐明。在这里，我们报道过在 HepG2 肝细胞中过氧化物酶体增殖物激活受体-γ（PPARγ）可增加 NEDD4 mRNA 和蛋白水平。PPARγ 拮抗剂 GW9662 可消除噻唑烷二酮（TZD）诱导的 NEDD4 表达。染色质免疫沉淀和荧光素酶报告基因检测表明，PPARγ 可直接结合人 NEDD4 基因启动子区域内的潜在 PPAR 反应元件（PPREs）。此外，TZD 可增加 Akt 磷酸化和葡萄糖摄取，而通过 NEDD4 耗竭可消除这种作用。此外，我们还表明，NEDD4 介导的自噬诱导和 Akt 磷酸化可被油酸和高葡萄糖处理抑制，而激活 PPARγ 可成功阻止这种抑制。总之，这些结果表明，PPARγ 通过 NEDD4 对自噬机制的影响，在将葡萄糖代谢与蛋白质稳态联系起来方面发挥着新的作用。
